Breast cancer is the second leading cause of death in females with cancer. In 2013 approximately 232,340 new cases of invasive breast cancer were diagnosed, where an estimate of 39,620 was expected to succumb to their disease. It is estimated that one in eight women will develop breast cancer in their lifetime. Breast cancer is classified into subtypes based on the expression of estrogen receptor (ER), progesterone receptor (PR) and amplification of human epidermal growth factor receptor 2 (HER2). The presence or absence of these molecular markers has been used to estimate clinical prognosis and to determine treatment response to current breast cancer therapies targeting these pathways. Despite these therapeutic advances, breast cancer patients that have undetectable ER, PR and HER2, known as triple negative breast cancer (TNBC) cannot benefit from these targeted treatments. Cytotoxic chemotherapy continues to be the primary treatment option for TNBC patients, which typically have poor prognosis and significantly lower overall survival when compared to patients that are ER and/or PR positive. Thus, there is a major unmet medical need to develop effective long-term therapies for resistant breast cancers, including TNBC. Resistant tumors are able to survive and thrive in the hostile tumor microenvironment with low nutrients and oxygen by adapting to such toxic milieu through various survival mechanisms, such as sustained unfolded protein response (UPR) or persistent endoplasmic reticulum stress (ERS), and autophagy. The hallmark of ERS is the enhanced expression of chaperone proteins that facilitate the clearance of misfolded proteins, and as a result they promote anti-apoptotic mechanisms and enhance cancer cell survival. The overexpression of these chaperone proteins can also confer resistance towards cytotoxic chemotherapy. Therefore, it is not surprising that tumor cells with chronic low level of ERS are able to survive and even thrive in inhospitable environments, including cytotoxic chemotherapy. This project is supported by our findings that even a small increase in the ER stress levels in tumor cells can surpass a certain threshold where it triggers apoptotic cell death specifically in tumor cells. Based on our investigations of this novel concept, we identified a lead compound, which was shown to have efficacy and safety profile suitable to advance for human evaluation. This small molecule was found to be active in a wide range of cancers including, lung, brain, breast, and colon cancers, and was shown to be active alone and in combination with conventional chemotherapy in TNBCs. This project will support the advancement of our lead compound towards clinical development. This will be accomplished by establishing the optimal dosage and frequency when used alone and in combination with cytotoxic chemotherapy, and by determining its pharmacokinetics and pharmacodynamics. These efforts will set the stage for completing the preclinical studies of this promising compound, and will help advance it towards clinical studies for resistant breast cancers, including TNBC.